FDA advisories warning of increased suicide risk among children and adolescents beginning antidepressant therapy have alarmed the health care community. But emerging evidence suggests that this may not be the case--and that it may actually be a disservice to withhold these medications from persons who need them.
Recent observational evidence of reduced suicide risk in persons beginning antidepressant therapy stands in direct opposition to FDA advisories associating these agents with suicidality. This finding also raises the question of whether more patients will be at risk if FDA advisories and the black box warning serve to discourage antidepressant use, rather than--as intended--to encourage their careful monitoring.
Simon and colleagues1 evaluated health plan data (1992 to 2002) for more than 65,000 patients receiving their first antidepressant for a depressive episode. For both adults and adolescents, the risk of suicide was highest in the month before starting the antidepressant, and decreased progressively with continued treatment. The patterns . . . appear more consistent with a decline in suicide risk after initiation of treatment, than they are with a medication-induced increase, the investigators observed. The decline in suicide attempts . . . closely parallels the trend in depressive symptoms seen in patients who receive new antidepressant prescriptions.
The month before this study appeared in the literature, Donald Klein, MD, of the New York State Psychiatric Institute, Columbia University, published his concern about an uncertain public health impact from the sharp decrease in antidepressant prescriptions that followed issuance of a blackbox warning in October 2004 advising physicians of possible increased suicide risk in children.2,3 There is no convincing evidence that antidepressants specifically increase suicide attempts, Klein declared. The [FDA] committee's decision was probably influenced by the paucity of data, except for fluoxetine, demonstrating a specific benefit. In terms of a risk-benefit ratio, the lack of specific benefit became misleadingly translated into a high specific risk.2
Amid disputes over issues of suicide risk and data validity, researchers continue to investigate whether antidepressants can be deadly. The randomized clinical trial is the gold standard for discerning drug effect, but the trial size necessary to detect a relatively rare event--along with the ethical necessity and methodologic difficulty of establishing a valid surrogate marker of suicidality, rather than waiting to detect a suicide attempt--make it unlikely that a clinical trial can resolve the question. Multiple trials can provide a large number of persons to assess, but measures may be inconsistent across studies and the behavioral measures may be unreliable markers of suicide.
In his article, Klein faulted the FDA for issuing suicide warnings about antidepressants based on the results of diverse clinical trials using inconsistent, post hoc determinations of suicidality as surrogate markers for completed suicide. It was only by the amalgamation of diverse trials and questionable variables, of unlikely clinical or predictive significance, that statistical sanctification was approached, he asserted.
An alternative approach, used by Simon's group and others, is to examine patterns of antidepressant use and suicide in large populations over time. However, confirming or excluding a causal relationship remains difficult, especially if the alleged drug effect could also be caused by the condition the drug is designed to treat (confounding by indication), as is the case with suicide and depression.4 The observational studies that control for selection bias related to particular drug use and non-drug-related risks of suicidal behavior can provide only partial insight into the issues, according to Simon and colleagues.1 For a study of suicide death or serious suicide attempts, it will be necessary to rely on multiple sources of data, they indicated, including both large observational studies and randomized trials.1
1. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry. 2006;163:41-47.
2. Klein DF. The flawed basis for FDA post-marketing safety decisions: the example of anti-depressantsand children. Neuropsychopharmacology. December 14, 2005; [Epub ahead of print].
3. FDA public health advisory: suicidality in children and adolescents being treated with antidepressant medications. October 15, 2004. Available at: http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm. Accessed February 22, 2006.
4. Didham RC, McConnel DW, Blair HJ, Reith DM. Suicide and self-harm following prescriptions of SSRIs and other antidepressants: confounding by indication. Br J Clin Pharmacol. 2005;60:519-525.
5. FDA public health advisory: worsening depression of suicidality in patients being teated with antidepressant medications. March 22, 2004. Available at: http://www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm. Accessed February 22, 2006.
6. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292: 338-343.
7. Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and nonfatal self harm in first episode depression: nested case-control study. BMJ. 2005;330:389.
8. Valuck RJ, Libby AM, Sills MR, et al. Antidepressant treatment and risk of suicide attempt by adolescents
with major depressive disorder: a propensityadjusted retrospective cohort study. CNS Drugs. 2004;18:1119-1132.